Perivascular Inflammation Research Articles

Unique Presentations of Burkholderia gladioli Infections in Several Strains of Immunocompromised Mice.

Four strains of experimentally naïve mice (NOD. Cg-Prkdc scid Il2rg tm1Wjl /SzJ [NSG], NOD. Cg- Rag1 tm1Mom Il2rg tm1Wjl /SzJ [NRG], B6.129S(Cg)-Stat1 tm1Dlv/J [STAT1 -/-], and B6.129S7- Ifngr1 tm1Agt/J[IFNγR -/-] housed in a barrier facility developed unusual and seemingly unrelated clinical signs. Young NSG/NRG mice (n = 49, mean age = 4 ± 0.4 mo) exhibited nonspecific clinical signs of moderate-to-severe lethargy, hunched posture, decreased body condition, and pallor. In contrast to the NSG/NRG mice, the STAT1-/- and IFNγ R-/- mice (n = 5) developed large subcutaneous abscesses on the head and neck. These mice were euthanized, and samples were collected for culture. NSG/NRG mice had moderate-markedly enlarged livers (20 of 49, 40%) and spleens (17 of 49, 35%). The livers contained multiple, variably-sized, tan regions throughout all lobes. Histology revealed necrotizing hepatitis (13 of 17, 77%), splenic and hepatic extramedullary hematopoiesis (17 of 17, 100%), glomerular histiocytosis (6 of 17, 35%), and metritis (6 of 11, 55%) with perivascular inflammation, suggesting hematogenous spread Differentials for these lesions included mouse hepatitis virus, ectromelia virus, Pseudomonas aeruginosa, Salmonella spp., and Clostridium piliforme. Burkholderia gladioli was cultured from liver lesions and subcutaneous abscesses and confirmed with 16S ribosomal RNA sequencing. After completing systematic testing of the environment, failure of the water autoclave cycle was suspected as the cause of the outbreak. To address the situation, individually ventilated racks were sanitized and new breeders were purchased; these actions dramatically reduced B. gladioli infections. The current literature contains few reports of B. gladioli infections in immunocompromised mice, and its typical presentation is torticollis and rolling. B. gladioli infection is a potential differential for subcutaneous abscesses, hepatitis, and splenomegaly in immunocompromised mice. Careful monitoring of sterilization techniques is essential to prevent such infections in a barrier facility.

Comparison of Muscle Biopsy Features with Myositis Autoantibodies in Inflammatory Myopathies: A Pilot Experience

Abstract Background: Idiopathic inflammatory myopathies (IIM), also called autoimmune myositis, are heterogeneous. These include dermatomyositis (DM), inclusion body myositis, immune mediated necrotizing myopathy (IMNM), anti-synthetase syndrome (ASS), and overlap polymyositis. Classification of IIM has evolved from clinical to clinico-pathologic to the recent clinico-sero-pathologic with the discovery of myositis-specific antibodies (MSA) and myositis-associated antibodies. The various antibodies have shown association with specific phenotypes. Objective: To analyze muscle biopsy features with respect to each MSA and MAA to understand the frequency of findings in each entity. Materials and Methods: Biopsy-proven cases of IIM where myositis profile was available were included in the study after obtaining Institutional Ethics Committee (IEC) approval. In addition to the stains and enzyme histochemistry, immunohistochemistry with MHC class I and II and MxA was performed. Features like perifascicular atrophy, perifascicular necrosis, scattered necrosis, inflammation, etc. were analyzed. Myositis profile was performed by line-blot technique using a 16-antigen panel. Cases were divided into different autoantibody subgroups. Various clinical, demographic, and muscle biopsy features were studied with respect to each MSA and MAA. Results: There were a total of 64 cases. Mi2 (N = 18) was the most common autoantibody. Some of the salient observations included PFA with perivascular inflammation in Mi2; pediatric cases and microinfarcts in NXP2; no PFA or inflammation in MDA5; perifascicular necrosis in JO1; extensive necrosis with sparse inflammation in SRP; more inflammation in overlap myositis; MxA positivity in DM; and absent in ASS. Conclusion: This is a pilot study documenting differences in biopsy phenotype with each MSA and MAA which is comparable to the literature. These findings can be used to characterize IIM in seronegative biopsies.

Immunomodulatory effect of IL-2 induced bone marrow mononuclear cell therapy on control of allergic asthma.

Asthma is a chronic airway disease. Allergic reactions and T helper (h)2 immune response play a key role in asthma occurrence. Cell therapy can control inflammation and remodeling responses in allergic asthma, and cytokines can change this effect. Therefore, in this study, the effect of treated cell therapy with IL-2 to control allergic asthma was studied. Bone marrow cells were extracted and co-cultured with IL-2 and the cells were used via intra-tracheal administration in allergic asthma mice. Levels of IL-4, IL-5, IL-13, Leukotriene B4 and C4, and remodeling factors were measured. At least, a histopathology test of lung tissue was done. Type2 cytokines, leukotrienes, remodeling factors, mucus secretion, goblet cell hyperplasia, peri-bronchial and peri-vascular inflammation were significantly (p˂0.05) decreased by treating with bone marrow-derived mononuclear cells (BMDMCs) and IL-2-BMDMCs. Treatment with IL-2-BMDMCs could significantly decrease IL-13, transforming growth factor (TGF)-β, HP levels, and mucus secretion (p˂0.05) compared to BMDMCs treatment. In this study, BMDMCs and IL-2-BMDMCs therapy could decrease inflammation, allergic, and remodeling factors in allergic asthma. Cell therapy with BMDMCs had a strong and notable effect on the control of allergic asthma pathophysiology when co-cultured and used with IL-2.

Squamous Cell Carcinoma Arising in Lesions of Discoid Lupus Erythematosus in a Patient with Overlap Syndrome: A Chronic Rare Complication.

Squamous Cell Carcinoma Arising in Lesions of Discoid Lupus Erythematosus in a Patient with Overlap Syndrome: A Chronic Rare Complication.

S-07-7: ANGIOTENSIN, VASCULAR AGING AND HYPERTENSION

Aging is a major non-modifiable risk factor underlying hypertension and associated cardiovascular disease. With aging, the vasculature undergoes structural, functional and mechanical alterations characterized by endothelial dysfunction, media thickening, reduced distensibility, and arterial stiffening. Many of these processes are associated with activation of the renin angiotensin aldosterone system (RAAS), which is characteristically associated with the pathophysiology of hypertension. In particular Ang II, through the AT1 receptor, and aldosterone through the mineralocorticoid receptor, activate pro-inflammatory and pro-fibrotic signaling pathways that lead to vascular fibrosis, extracellular matrix (ECM) deposition, arterial remodelling, perivascular inflammation and hyperreactivity. These processes are also associated with aging and are amplified by hypertension. Molecular mechanisms underlying these events include increased expression and activation of matrix metalloproteinases, activation of transforming growth factor1/SMAD signalling, upregulation of galectin-3, activation of aging signaling pathways, eg p66Shc, c-Src, and oxidative stress. Fundamental to these processes is phenotypic switching of vascular smooth muscle cells from a contractile to de-differentiated state. This involves epigenetic changes and alterations in the vascular proteome. Complex interplay between the “aging process” and prohypertensive factors, including Ang II and aldosterone, result in accelerated vascular remodelling and fibrosis and increased arterial stiffness, which is typically observed in hypertension. Because the vascular phenotype in a young hypertensive individual resembles that of an elderly otherwise healthy individual, the notion of “early” or “premature” vascular aging is frequently used to describe hypertension-associated vascular disease. This presentation discusses the vascular phenotype in aging and hypertension and the role of the RAAS. In addition novel molecular mechanisms, focusing on oxidative stress and the vascular proteome will be highlighted.

Study effect of MAPA-VIP on control of allergic asthma pathophysiology.

Asthma is a pulmonary disease and its pathogenesis is involved with immune cells and related signalling pathways. Alpha-alumina is material for therapy applications and mucus adhesion promoting protein is cell-surface protein. Vasoactive intestinal peptide (VIP) exerts immunomodulation. Therefore, the drug delivery system and target binding molecule could be applicable for treatment of asthma. VIP-MapA-α-alumina was administered to asthmatic mice. Then, eosinophil percentage, IgE, IL-4, IL-5, and IL-13 levels, GATA3, and MUC5AC gene expression, ROS and lung histopathology were studied. Eosinophil percentage, IgE, IL-4, IL-5, IL-13, and ROS levels, expression of GATA3 and MUC5AC genes, goblet cell hyperplasia, mucus hyper-production, perivascular and peribronchial inflammation were decreased in VIP and VIP-MapA treated groups and treatment with VIP-MapA has a stronger effect than VIP alone. The delivery system of VIP carrying to the lung with the use of MapA as an adhesion molecule, could easily carry VIP and led to penetration of this component to the mucus and reach bronchial cells and present an effective, strong, and long-acting effect on therapy of asthma.

Coronary perivascular adipose tissue inflammation – An autopsy-based histomorphological study from a tertiary care hospital in South India

Background: The connective tissue around the blood vessels in the body (except cerebral vessels) is called perivascular adipose tissue (PVAT). Whenever there is a vascular pathology, PVAT increases in volume and becomes dysfunctional. This change promotes dedifferentiation of adipocytes. PVAT inflammation (PVATi) starts secreting anti-vasodilation and pro-inflammatory substance, leading to infiltration of inflammatory immune cells, endothelial dysfunction which initiates atherosclerosis followed by stenosis. It is now recognized that PVATi plays an important role in many vascular pathologies. Aims and Objectives: The objectives of the study were (1) to estimate the prevalence of coronary PVATi in an autopsy case, (2) to determine the coronary atherosclerotic changes and cardiac changes associated with PVATi, and (3) to correlate the association of PVATi with age and sex. Materials and Methods: Autopsy-based retrospective study done for a period of 1 year. From the autopsy requisition form, details such as age, gender, cause of death (COD), and gross findings of the organs were noted. The left coronary artery, right coronary artery, left anterior descending artery, left circumflex artery, and myocardium slides were reviewed microscopically to note the presence of PVATi, type of inflammatory infiltrate, atherosclerotic changes, percentage of stenosis, and associated cardiac changes. Range, frequencies, percentage, mean, standard deviation, and P-value were calculated. P<0.05 was taken as statistically significant. Results: Fifty-two cases showed PVATi among 400 autopsy cases performed during the period of 1 year. Forty-two cases were from males and 10 cases were from female. The most common COD noted was sudden death following chest pain. Ten cases showed PVATi involving major branches of the coronary artery. Thirty-six cases showed hypertrophic changes in myocardium. Acute myocardial infarction (MI) and old healed MI were noted in 7 and 23 cases, respectively. Conclusion: PVATi of coronary arteries has significant association with atherosclerosis and sudden death cardiac death.

PS-BPB04-8: ANGIOTENSIN II FORMULATIONS AND THEIR IMPACT ON CARDAIC, VASCULAR AND INFLAMMATORY MECHANISMS OF HYPERTENSION

Angiotensin II (AngII) is a major effector of the renin-angiotensin system, with a critical role in BP regulation of vascular function, and end-organ damage. AngII infusion, using osmotic minipumps, is the most common animal model of hypertension, recapitulating key vascular and cardiac features of human hypertension. While different formulations of AngII are available, their impact on the key outcomes of the model remains unknown. Accordingly, we compared two most commonly used AngII formulations, and their impact on the key cardiovascular endpoints in a mouse model of hypertension. Male 12-week old C57BL/6J mice (n = 11–14) underwent Sham, AngII[Val5] or AngII[Ile5] (490 ng/min/kg) treatment for two weeks, using osmotic minipumps. Blood pressure was measured by tail-cuff, vascular function by wire myography, remodelling by picrosirius red staining, mRNA expression using real-time PCR and perivascular (PVAT) inflammation by flow cytometry. Data were analyzed using one-way or RM-two-way ANOVA. Both AngII formulations caused a significant BP elevation (p < 0.001) in comparison to sham animals, although AngII[Val5] had a more pronounced pressure effect than AngII[Ile5] (171 ± 4 vs 156 ± 6 mmHg, p = 0.03). Similarly, endothelium-dependent relaxation of resistance arteries and aorta was significantly impaired by AngII infusion (p < 0.001), however, a maximum Ach-induced relaxation was significantly lower in AngII[Val5] than in AngII[Ile5]. Both, AngII formulations increased intima-media thickness of the aorta (p < 0.0001), although the effect of AngII[Val5] was ∼2-fold higher than AngII[Ile5] (p = 0.001). While animals infused with AngII[Val5] had enhanced vascular collagen deposition (p < 0.001), this effect was lesser in the AngII[Ile5] group (p = 0.02). The total number of leukocytes infiltrating PVAT was induced by both AngII formulations, however, this effect was less pronounced in AngII[Ile5] (1002 ± 376 vs. 753 ± 242 cell/mg, p = 0.03). The same effect was found among CD11b+ and CD11c+ cells. While a significant increase of CD3+ cells was observed in both AngII formulations. While cardiac hypertrophy was evident in both AngII formulations this effect was significantly lower in AngII[Ile5] (p = 0.03). This was confirmed by cross-sectional area of cardiomyocytes. Histological analysis of heart sections showed a significant effect of both AngII formulation on cardiac fibrosis (p < 0.05). This effect was more pronounced upon AngII[Val5] infusion (p < 0.001) and was associated with higher expression of pro-fibrotic markers. AngII[Val5] formulation is a more efficient and consistent way to study key cardiovascular endpoints such as BP, inflammation, vascular and cardiac damage compared with AngII[Ile5]. Furthermore, the use of AngII[Val5] leads to a more pronounced phenotype and may be associated with reducing the number of animals needed in experiments.

PS-B10-6: CAPILLARY-TO-ARTERIOLAR SIGNALLING, INFLAMMATION AND SMALL VESSEL DISEASE OF THE BRAIN

Objective: Chronic cerebral inflammation is thought to be a mechanism by which hypertension causes small vessel disease of the brain, leading to dementia. Mouse studies have demonstrated enhanced small resistance artery constriction and neurovascular uncoupling in hypertension. We wished to examine whether acute exposure to the predominant inflammatory driver in hypertension, interleukin-1β; (IL-1β;) could account for this dual vascular deficit. Design and method: Pressure myography of freshly isolated mouse posterior cerebellar pial arteries was used to assess contributions of the inwardly rectifying K+ 2.1 (KIR2.1) channel to vasodilation. In order to assess neurovascular coupling from a vascular perspective, we adopted a recently described approach: the Capillary to Parenchymal Arteriole (CaPA) preparation. In the CaPA preparation, penetrating arterioles (< 40ums) with attached capillary branches are isolated and pressurised. The capillary branch and arteriole are independently stimulated via a micropipette and arteriole diameter is recorded. This approach enables the retrograde hyperpolarising signal from the KIR2.1 channel, which propagates against the flow of blood in the brain, to be assessed both in terms of the extent of arteriole vasodilation and the speed of communication (video). In order to assess the effects of perivascular inflammation on cerebrovascular function, we incubated (in culture medium) small pial arteries with IL-1β; for 24 hours prior to study on a pressure myograph rig. KIR2.1 function was assessed using 10 mM exogenous K+. Cerebral arterioles with attached capillaries were incubated with IL-1β; for 2 hours prior to CaPA study. We then examined the capillary-to-arteriolar signalling mechanism via application of 10 mM K+ to the capillary. We also assessed arteriolar tone and reaction to directly applied K+, NS309 and U46619. Results: Preliminary data suggests that sub-acute incubation with exogenous IL-1β; had no effects on the degree of pressure induced constriction of either the pial artery or the arteriole. CaPA preparation showed that the KIR2.1 capillary-to-arteriolar signalling was preserved as well as arteriolar responses to direct K+, NS309 and U46619 following IL-1β; exposure. Conclusions: Whilst chronic cerebral inflammation in the setting of hypertension results in cerebrovascular deficits, sub-acute exposure with IL-1β; does not appear to significantly impair cerebral microvascular function. Precisely how chronic exposure to inflammation in hypertension induces neurovascular uncoupling is the subject of ongoing investigation.

Carotidynia or Transient Perivascular Inflammation of the Carotid Artery (TIPIC): A 5 O'Clock Shadow.

Carotidynia or Transient Perivascular Inflammation of the Carotid Artery (TIPIC): A 5 O'Clock Shadow.

The Ongoing Myth of TIPIC-Syndrome

Carotidynia is characterized by intense localized pain and tenderness at the level of the carotid bifurcation. The differential diagnosis is broad and includes vascular pathologies, infectious diseases or malignancies. Recent evidence now suggests a distinct entity called Transient Perivascular Inflammation of the Carotid Artery or TIPIC syndrome. The diagnosis is made per exclusionem and is based on typical radiological findings. This paper describes the clinical examination, laboratory results, radiological findings and treatment based on two case reports. TIPIC syndrome is an idiopathic syndrome which is usually a self-limiting disease of which a vascular surgeon should be aware.

Ultrasonic findings of transient perivascular inflammation of the carotid artery syndrome: a case report

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Unusual Association of Non-paraneoplastic Variant of Lambert-Eaton Myasthenic Syndrome with Predominant B-cell Inflammatory Myopathy

Introduction: Myasthenia gravis disease (MGD) and inflammatory myopathy (IM) are commonly reported in the literature and usually appear with thymic pathology. Lambert-Eton myasthenic syndrome (LEMS) associated with IM is extremely rare. Case Presentation: We report a 42-year-old female patient who presented with proximal muscle weakness of the upper and lower limbs, normal creatinine kinase (CK) level, and positive acetylcholine and voltage-gated calcium channel receptor antibodies. There were no oculobulbar symptoms and no history of thymoma, and the electrophysiological tests were unremarkable. Muscle biopsy revealed focal perimysial and perivascular inflammation, predominantly B-cell lymphocytes, in a non-necrotizing muscle. Conclusions: LEMS associated with IM, particularly B-cell inflammation, has never been reported in the absence of cancer history. Clinical investigations and myopathological features can help establish the diagnosis.

Treatment-Refractory Autoimmune Glial Fibrillary Acidic Protein Meningoencephalomyelitis in a Young Adult Female

Objective To describe a case of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy refractory to immunotherapy without evidence of malignancy or coexisting autoimmunity. Background Autoimmune GFAP astrocytopathy is an autoimmune disease of the central nervous system associated with the presence of GFAP-IgG in the CSF. Patients may present with acute or subacute onset of headache, encephalopathy, seizures, abnormal vision, weakness or numbness, postural tremor and cerebellar ataxia. GFAP astrocytopathy is usually corticocorticosteroid-responsive in the acute setting but may rarely require maintenance immunotherapy to prevent relapse. Treatment refractory cases should trigger work up for coexisting autoimmunity or malignancy. Design/Methods A 35-year-old female patient presented with subacute meningoencephalomyelitis with prodromal symptoms. Results Her cerebrospinal fluid revealed lymphocytic pleocytosis and elevated protein. Brain magnetic resonance imaging (MRI) with and without contrast showed perivascular radial enhancement and periventricular T2 FLAIR hyperintensity. Spinal MRI with and without contrast demonstrated longitudinal T2 FLAIR hyperintensity from T1-T2 to T7-T8. Despite high dose steroid treatment, her disease progressed with an enlarging periventricular lesion and worsening visual acuity. Biopsy of the enhancing periventricular lesion showed perivascular inflammation. After five cycles of plasma exchange along with a five-day course of intravenous methylprednisolone 1 gram daily, her symptoms stabilized. The CSF autoimmune encephalopathy panel (Mayo Clinic Laboratories) came back positive for GFAP-IgG antibody on tissue immunofluorescence assay, and was confirmed positive by GFAP cell-based assay. No neoplastic disease was identified using high resolution PET/CT scans. Based on the aggressiveness of her disease, she received one cycle of cyclophosphamide, and was discharged home on an oral corticosteroid taper. Even one year after addition of both mycophenolate mofetil and rituximab, MRI imaging continued to reveal new enhancing lesions. Conclusions Autoimmune GFAP astrocytopathy may sometimes require long-term immunosuppression even without presence of malignancy or other coexisting autoimmune disease.

A Rapidly Fatal Case of Anti-GFAP Receptor Encephalitis Due to Acute Brain Edema and Herniation

Objective Glial fibrillary acidic protein antibody (GFAP) is a newly recognized biomarker for an immunotherapy responsive autoimmune meningo-encephalomyelitis with a wide variety of clinical presentations. We report the second GFAP antibody positive case in a young man who died despite appropriate and aggressive immunomodulatory treatment. Background 29 year old previously healthy male with childhood immune disorder presented with 3 week history of acute progressive worsening headaches, bloody emesis, nausea, blurry vision and generalized weakness. Exam was significant for downbeating nystagmus, limb ataxia and tremor and later progressing into inattention, confusion, urinary retention, asymmetric pupils, hyprreflexia and lack of motor or sensory response. Lumbar puncture revealed lymphocytic pleocytosis with elevated protein and opening pressure of 36 cm H20. MRI demonstrated areas of restricted diffusions symmetrically involving white matter of the corpus callosum, middle cerebellar peduncle, cerebellar white matter bilaterally as well as within the pons centrally. Patient was started on intravenous immunogammaglobulin (IVIG) and pulse corticosteroids along with broad spectrum antimicrobial therapy. After an initial apparent response to treatment, repeat head CT showed Diffuse Sulci effacement. Shortly after, He rapidly decompensated with clinical findings indicating brainstem herniation, cardiac arrest and brain death was diagnosed. CSF studies subsequently were reported as positive for GFAP antibodies. An autopsy reported the cause of death as cerebellar tonsillar herniation secondary to diffuse cerebral edema. all sections showed perivascular inflammation and gliosis. Design/Methods NA. Results NA. Conclusions This reported case of anti-GFAP meningo-encephalomyelitis is unusual for the rapid onset of cerebral edema and rapid progression to herniation and brain death occurring only 4 weeks after symptom onset. While this may be a rare complication of Anti GFAP encephalitis, clinicians should be vigilant for acutely increased intracranial pressure in patients with clinical findings of encephalitis in general.

Eosinophils protect against pulmonary hypertension through 14-HDHA and 17-HDHA.

Pulmonary hypertension (PH) is a life-threatening disease featuring pulmonary vessel remodelling and perivascular inflammation. The effect, if any, of eosinophils (EOS) on the development of PH remains unclear. EOS infiltration and chemotaxis were investigated in peripheral blood and lung tissues from pulmonary arterial hypertension (PAH) patients without allergic history and from sugen/hypoxia-induced PH mice. The role of EOS deficiency in PH development was investigated using GATA1-deletion (ΔdblGATA) mice and anti-interleukin 5 antibody-treated mice and rats. Ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was conducted to identify the critical oxylipin molecule(s) produced by EOS. Culture supernatants and lysates of EOS were collected to explore the mechanisms in co-culture cell experiments. There was a lower percentage of EOS in peripheral blood but higher infiltration in lung tissues from PAH patients and PH mice. PAH/PH lungs showed increased EOS-related chemokine expression, mainly C-C motif chemokine ligand 11 derived from adventitial fibroblasts. EOS deficiency aggravated PH in rodents, accompanied by increased neutrophil and monocyte/macrophage infiltration. EOS highly expressed arachidonate 15-lipoxygenase (ALOX15). 14-hydroxy docosahexaenoic acid (14-HDHA) and 17-HDHA were critical downstream oxylipins produced by EOS, which showed anti-inflammatory effects on recruitment of neutrophils and monocytes/macrophages through N-formyl peptide receptor 2. They also repressed pulmonary artery smooth muscle cell (PASMC) proliferation by activating peroxisome proliferator-activated receptor γ and blunting Stat3 phosphorylation. In PH development without external stimuli, peripheral blood exhibits a low EOS level. EOS play a protective role by suppressing perivascular inflammation and maintaining PASMC homeostasis via 14/17-HDHA.

INNV-23. MANAGING CENTRAL NERVOUS SYSTEM MANIFESTATIONS OF CHRONIC GRAFT VERSUS HOST DISEASE FOLLOWING HEMATOPOIETIC STEM CELL TRANSPLANTATION: A CASE REPORT

Abstract Central nervous system (CNS) manifestation of chronic graft versus host disease (cGVHD) is a rare, difficult to diagnose phenomenon that can follow allogeneic hematopoietic stem cell transplantation (HSCT). CNS-cGVHD typically onsets 2-31 months post-transplant, involves diffuse infiltration of inflammatory cells, demyelination, and cerebral vasculitis, and is associated with an extremely poor prognosis. We present a case of a 37-year-old man who developed seizures, myopathy, bilateral upper and lower extremity weakness, confusion, and irritability almost 2 years after HSCT for acute myeloid leukemia (AML). CNS-cGVHD diagnosis was confidently determined via magnetic resonance imaging (MRI) demonstrating enhanced focal white matter lesions, cerebrospinal fluid (CSF) studies demonstrating elevated globulin (12.7 mg/dL; normal range: 0-6 mg/dL) and elevated immunoglobulin G (IgG) synthesis rate (13.9 mg/d; normal range: ≤ 8 mg/d), and a right brain biopsy demonstrating encephalitis, perivascular inflammation, microglial activation, and gliosis with predominately intramural and perivascular CD3+ T-cells, CD4+ and CD8+ cells. Complete resolution of neurological symptoms, including seizures, was achieved with a combination of steroids, ibrutinib, intravenous immunoglobulin (IVIG), and anti-seizure medications. Improvements to CNS-cGVHD was further indicated by normalized MRI studies without abnormal enhancements and improved CSF studies with reduction in globulin levels (11.3 mg/dL) and complete normalization of IgG synthesis rate (≤ 0 mg/d). It is imperative that CNS-cGVHD be considered in patients that present with neurological signs post-transplant. An early, confident diagnosis generates prompt intervention and as demonstrated, can lead to complete resolution of neurological symptoms.

Abstract 13194: Towards Understanding the Pathogenesis of Covid-19: Acute and Long-Term Mouse Models

SARS-CoV2 (CoV2) infection causes both acute and long-term health effects via damaging multiple organs including lung. The endothelial dysfunction associated with the infection may contribute to pathogenesis of acute COVID-19 and long COVID. However, the mechanisms underlying the endothelial dysfunction remain elusive. Development of mouse models for these diseases will help us better dissect these mechanisms and facilitate the development of therapeutics for treatment of the disease. Previously, we developed an acute COVID model by infecting human ACE2 transgenic (K18) mice with a lethal CoV2 dose. K18 mice developed severe COVID-19, including progressive body weight loss and fatality at days 7 post infection (DPI), severe lung interstitial inflammation, edema, hemorrhage, perivascular inflammation, systemic lymphocytopenia, and eosinopenia. We detected CoV2 in capillary endothelial cells, activation and adhesion of platelets and immune cells to the vascular wall of the alveolar septa, and increased complement deposition in the lungs in this model. These results indicate that CoV2 infection and infection-mediated immune activation caused endothelial dysfunction, which contributes to the pathogenesis of severe COVID-19. To further develop a model for long COVID, we infected K18 mice with sub lethal CoV2 dose, monitored the body weight and survival rate and characterized the lung and brain histological changes at 21 and 45 DPI. The infected mice progressively lost body weights from 5 to 7 DPI and started to rebound from 8 DPI and then returned to baseline at 13 DPI. Mice had extensive patchy inflammation in the lungs associated with collagen deposition and smooth muscle action expression. We also found moderate levels of total viral RNA in the lung but not brain while viral subgenomic RNA (a correlate of viral replication) was undetectable in lung or brain by qRT-PCR assay. Fluorescence staining showed co-localization of CoV2 spike protein and CD206 in lungs, suggesting macrophage engulfment CoV2 at late time points. Together, we have successfully established long-term COVID mouse models, which will be useful tools for further defining the role of endothelial dysfunction in pathogeneses of CoV2-related acute and long COVID.

Abstract 14984: Transient Constrictive Pericarditis: Pericardiectomy to the Rescue

Case Presentation: A 47 years old male presented with progressive dyspnea, bilateral leg and abdominal swelling, weight gain, and intermittent low-grade fever. He had a history of hypertension and chronic lymphocytic pericarditis complicated by an episode of constrictive pericarditis. Exam showed jugular venous pressure of 10 cmH2O, pericardial knock, and abdominal distention. Inflammatory markers were elevated (CRP 87.3 mg/dL, ESR 29 mm/hr). Echo showed abnormal increase in septal longitudinal motion and Doppler interrogation of the hepatic veins showed diastolic flow reversal at the end of expiration. Cardiac MRI showed pericardial thickening and circumferential delayed pericardial enhancement. Patient was diagnosed with transient constrictive pericarditis (TCP) and was treated with ibuprofen, colchicine, and prednisone and had improvement in his symptoms and inflammatory markers. However, he experienced another recurrence 6 months later and underwent pericardiectomy. Pathology showed organized fibrosis overlying the parietal fibrosa layer, mild neovascularization and perivascular chronic inflammation, confirming the diagnosis of TCP. After pericardiectomy, patient had significant symptomatic improvement and returned to his baseline activity level. Postoperative echo showed normalization of annulus longitudinal motion and cardiac MRI showed near resolution of pericardial delayed enhancement. He was successfully tapered off of his anti-inflammatory regimen. Discussion: TCP is a sub-type of constrictive pericarditis characterized by pathological findings of pericardial edema, acute or subacute inflammation, and fibrin deposition, as opposed to the fixed pericardial fibrosis and calcification seen in constrictive pericarditis. Constriction may resolve spontaneously, and anti-inflammatory therapy is the mainstay of treatment but in refractory cases like these, pericardiectomy comes to the rescue.

Abstract 14566: The Role of Eosinophils in Pulmonary Hypertension

Introduction: Pulmonary hypertension (PH) is a severe life-threatening disease with insidious onset and high mortality, featured by pulmonary vascular remodeling and perivascular inflammatory cell infiltration. However, the precise immune mechanisms underlying PH remain unclear. Although an enhanced Th2 immune response in PH has been reported for years, the role of eosinophils (EOS), one of the Th2 effector cells, in PH is seldom reported. Investigating the roles and molecular mechanisms of EOS may present a novel paradigm of PH development. Hypothesis: EOS protect against PH through lipid metabolites. Methods: EOS infiltration and chemotaxis were investigated in peripheral blood and lung tissues from PH patients and sugen/hypoxia-induced PH mice. ΔdblGATA mice and anti-IL5 antibody (TRFK5)-treated mice were applied to investigate the role of EOS in PH development. Flow cytometry-based assays were used to quantify infiltration of different immune cells. The culture supernatants and lysates of EOS were collected to explore the mechanisms in co-culture cell experiments. Results: EOS accumulated in lung tissues from PH patients and mice, and the infiltration of EOS into pulmonary tissues during PH may be promoted by fibroblast-derived CCL11. Furthermore, EOS deficiency increased neutrophil (p=0.0038) and monocyte/macrophage (p=0.0344) infiltration and promoted pulmonary arterial smooth muscle cell proliferation, leading to aggravated PH in mice. Mechanistically, arachidonate 15-lipoxygenase (ALOX15), which catalyzes the production of pro-resolving lipid mediators, is specifically expressed by EOS. Conclusions: EOS play a beneficial role during PH development via ALOX15 and its downstream lipid mediators, suppressing perivascular inflammation and maintaining smooth muscle cell homeostasis.